Embolotherapy devices and reagents include metal embolic coils, gel foams, glues, oils, alcohol or particulate polymeric embolic agents used, for example, to control bleeding, prevent blood loss prior to or during a surgical procedure, restrict or block blood supply to tumors and vascular malformations, e.g., for uterine fibroids, tumors (i.e., chemo-embolization), hemorrhage (e.g., during trauma with bleeding) and arteriovenous malformations, fistulas and aneurysms. Embolic coils and particles are the most commonly used.
Conventional embolic coils are generally coiled metal strands that are constrained to a linear configuration during delivery through a vascular catheter. They have a geometrically pre-formed ‘coiled’ state to which they recover upon exiting the delivery catheter. There are a number of different design and procedural variations used with metal coils (see e.g., U.S. Pat. Nos. 6,358,228 and 6,117,157); however, metal embolic coils are designed to exploit the first response, i.e., a blood clot due to the hemodynamic response of a physical obstruction in the blood flow and in some cases an additional response i.e., a blood clot due to the biological response of the body to the coil material, wherein the therapeutic goal of the blocking the blood flow is accomplished by clot formation within and around the metal coil.
Although metal embolic coils have some advantageous physicomechanical properties, such as inherent radiopacity and shape memory (i.e., return to the preformed coiled state upon deployment), there are a number of disadvantages associated with the use of metal embolic coils, including inter alfa, chronic tissue damage, tissue hyperplasia, vessel occlusion and permanent incorporation into the tissue at the deployment site.
Non-metallic alternatives include liquid and particulate embolic agents. However, these also have significant disadvantages. Liquid embolic agents are generally divided into precipitative and reactive systems. In the former case, a polymer is solvated within a biologically acceptable solvent that dissipates upon vascular delivery leaving the polymer to precipitate in situ (see e.g., U.S. Pat. No. 5,851,508). Such agents may not precipitate quickly enough, thereby allowing a non-solidified (viscous) polymer embolic to migrate and embolize unintended tissues. This is of particular concern with arterio-venous malformations wherein the material can easily enter the venous system and cause a significant pulmonary embolism. Another disadvantage is the use of solvents, such as dimethylsulfoxide, for delivering the precipitative polymers.
Reactive embolic agents are primarily variations of cyanoacrylate chemical systems. An example of an FDA approved system is the TRUFILL® cyanoacrylate embolic from Cordis. Here, a liquid monomeric and/or oligomeric cyanoacrylate mixture is introduced to the vascular site through a catheter wherein polymerization is initiated by the available water in the blood. Unfortunately, if the dwell time during delivery is too great, the cyanoacrylate adhesive may bond the catheter tip to the tissues with grave consequences. A secondary concern is that the bioresorbable degradation products from these materials include formaldehyde, a toxic chemical.
Particulate therapeutic emboli are composed of particles of various size, geometry and composition. Schwarz et al., J. Biomater., 25(21), 5209-15 (2004) disclosed degradable hydroxy-ethyl acrylate (HEA) microspheres have been synthesized and tested in animals but none have been commercialized. The particles used for clinical applications are typically suspended in a radiopaque contrast solution and delivered through a vascular catheter via syringe injection. The three most common particulate embolic agents currently being used are GELFOAM® (absorbable gelatin particles from Pharmacia & Upjohn), polyvinyl alcohol (PVA) foam and trisacryl gelatin microspheres (EMBOSPHERE® from Biosphere Medical). Unlike metallic coils, these embolics are not inherently radiopaque. Indeed, placement visualization is dependent upon inference from fluoroscopic flow analysis during the embolic procedure. There is no direct ability to visualize the actual particles once inside the body. Also, in the case of PVA and EMBOSPHERE, the material may reside in the body throughout the patient's lifetime providing an increased risk of biological rejection. In the case of GELFOAM, there is the possibility of tissue rejection of this animal derived agent.
Particulate embolic agents may be used, for example, to restrict or block blood supply as in traditional applications which generally include delivery through a guide catheter such as treatment of tumors and vascular malformations, e.g., for uterine fibroids, cancerous tumors (i.e., chemo-embolization), hemorrhage (e.g., during trauma with bleeding) and arteriovenous malformations, fistulas and aneurysms.
Biocompatible, bioresorbable particulate embolic agents have the potential advantage of being temporary. The effective removal of the particulate foreign body over time allows the tissue to return to its unaffected state.
Radiopaque embolic particulate agents have the potential distinct advantage of being visible during and after embolic therapy procedures. During the procedure, visualization of the particulate agent would allow the physician to affect precise delivery to the targeted vessel or tissue. That is, the physician would be able to ensure that the particles do not become resident in unintended sites. This level of control would greatly enhance the safety and effectiveness of embolotherapy. Once the radiopaque particles have been implanted, follow-up procedures could be limited to non-interventional methods, e.g., simple X-Ray radiography. In the case of a tumor, for example, its size could be tracked since the radiopaque embolized sections would be shown converge as the mass/volume decreased with time.
As noted, biocompatible embolic particles exist on the market today. Indeed, bioresorbable biocompatible embolic agents are available in the form of GELFOAM®. As noted, however, there is a potential for rejection due to the animal origin of this material. Furthermore, GELFOAM® is not an FDA approved device for this application.
Attempts have been made to produce a more biocompatible degradable embolic particulate agent. Likewise, investigational radiopaque embolic agents have been produced and tested in animals for their potential utility. In all cases external agents such as iodinated contrast media or a metal or its salt (e.g., tungsten, barium sulfate, etc) must be added or inherent radiopacity imparted by halogenation of non-bioresorbable compositions.
Heretofore however, biocompatible, bioresorbable, inherently radiopaque particles for embolotherapy have not been conceived nor attempted. Accordingly, there remains an important unmet need to develop biocompatible, bioresorbable, inherently radiopaque particles for embolotherapy, which may also allow for repeat treatment of the same site, while circumventing or alleviating the foregoing disadvantages of existing or conceived particulate embolic agents.
Accordingly, there remains an important unmet need to develop bioresorbable, radiopaque embolic agents, wherein the polymeric materials used to fabricate these agents have the desirable qualities of metal (e.g., radiopacity), while circumventing or alleviating the foregoing disadvantages associated with the use of metal coils or liquid and particulate embolic alternatives.